Battling the Enemy on Many Fronts

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Effective vaccines have been developed to protect against all of these diseases. Yet over 20 years after HIV was identified as the cause of AIDS, we still lack an effective vaccine for this virus which causes over 5 million new infections and 3 million related deaths worldwide each year. The struggle to develop an effective vaccine against HIV is an ongoing collaborative research effort with many roadblocks, but also one in which we make considerable progress with each new approach tested in clinical trials.

Vaccines work by teaching the body's immune system to recognize and protect against future infection. One can envision it like giving a security guard a "mug shot" of a known criminal, so if anyone walks through the front door matching the picture, security would recognize that person and radio for backup, thereby preventing the crime.

Battling on Two Fronts

There are two ways in which an effective vaccine might work to arm the body with that "mug shot" or memory for HIV. First, and considered the best outcome of HIV vaccine research, is the induction of neutralizing antibodies. By prompting the immune system to produce these HIV-specific molecules, the vaccine effectively arms the body with the "mug shot." In the event of an infection, the antibodies would bind to HIV and prevent it from infecting human cells.

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Alternatively, the vaccine could aid the cells of the immune system to recognize and respond to HIV infection, which is called a cellular immune response. With the aid of the vaccine, two cell types of the immune system -- CD4+ and CD8+ T-lymphocytes (Helper and Killer T-cells) -- develop memory for HIV infection and then work together to recognize and destroy already infected cells. The first approach (eliciting neutralizing antibodies) aims to prevent infection while the second approach (eliciting T-cell immunity) aims to prevent progression to AIDS in the event of infection.

The difficulty in developing an HIV vaccine lies in the extreme variability of the virus, which makes it a complex target. For example, there are two basic types of HIV, HIV-1 which is causing most infections worldwide, and HIV-2, predominantly found in West Africa. Yet there are at least 9 different subtypes of HIV-1. North America and Western Europe have predominantly subtype B. India, China and South Africa have subtype C. Central Africa has a mixture of subtypes A, D, F, G, H, J, and K. With this kind of variability, it is unclear if a single vaccine would be effective against all strains worldwide.

Even within a single infected individual, HIV has the capacity to change or mutate, quickly adapting to threats like antiviral medications or the immune response itself. HIV is like the endlessly dividing broom in the classic animated film The Sorcerer's Apprentice, except that instead of making exact replicas of itself, HIV is an error-prone copy machine. Each copy may be a little different from its template. In this way, HIV has evolved mechanisms to avoid the immune response.

To avoid potentially neutralizing antibodies, HIV takes the main target of the antibodies and folds it up deep inside complex proteins found on the surface, called gp120 and gp41, like crumpling a grain of rice into a ball of aluminum foil; then HIV further covers itself in a shield of sugar, called glycosylation. HIV is only vulnerable to neutralizing antibodies when it is free floating in the blood and at the very moment of cell entry.

Once it infects a cell, HIV is inaccessible to the antibodies, but may then be vulnerable to the dynamic duo of CD4+ and CD8+ T-lymphocytes (Helper and Killer T-cells). To evade CD4+ and CD8+ T-lymphocytes, HIV preemptively infects and kills the CD4+ cells, depleting one of the main conductors of an orchestrated immune response. HIV then hides within some of the infected T-cells by pulling any evidence of infection below the surface. By doing so, HIV is able to hide within the infected cells, where it goes undetected by the immune defenses. There are also likely to be numerous other mechanisms that HIV has evolved to avoid the immune system that we are unaware of.

Fighting the Enemy

So, what are some of the approaches that are being tried against this elusive enemy? The goal of producing neutralizing antibodies will likely prove to be a greater challenge to vaccine development than a vaccine strategy based on strengthening the cellular immune response. For example, two large clinical trials attempting to induce an antibody response by injection of copies of the gp120 surface protein have proven ineffective, because of the elusive mechanisms of HIV mentioned above. Yet ongoing research at the Vaccine Research Center of the National Institutes of Health continues to study this approach by attempting to capture the virus just as the surface protein pulls back its sugar coating and unfolds itself to reveal the site where the HIV binds to the CD4+ lymphocyte. One can envision this innovative approach as driving a wedge in the aluminum ball as it unfolds so that the neutralizing antibodies can reach their target.

While the ultimate goal continues to be prevention of HIV infection, the majority of HIV vaccines currently being tested in clinical studies are designed to achieve the next best thing, which is to prevent people from getting sick should they acquire HIV infection. These vaccines are intended to elicit the CD4+ and CD8+ T-lymphocyte response which would attack HIV-infected cells. There are three steps to this approach: first, to capture and hold the attention of the T-lymphocytes, second to teach them what HIV looks like, and finally to repeat the lesson a few times so the response endures.

Two ways to capture the attention of the T-lymphocytes are the use of adjuvants and viral vectors. Adjuvants are substances commonly added to vaccines that act like a cup of coffee to wake up the immune system and accelerate, or enhance a specific response. Some adjuvants tested in HIV vaccine trials include those used in other vaccines such as alum and Freund's adjuvant. However, researchers are increasingly turning to our bodies' own natural immune stimulants, or chemokines, such as IL-2, IL-12, interferon gamma, and GM-CSF for use as adjuvants.

Another way to draw more attention to the vaccine is to hide the lesson (the components of HIV which will stimulate the immune response) inside another virus, called a vector. Viruses being used in this way include the canarypox, adenovirus, Venezuelan equine encephalitis (VEE), and modified vaccinia Ankara (MVA), each crippled so as not to cause infection themselves. Returning to the "mug shot" analogy, this approach is like a known petty thief quickly drawing attention to himself as he walks in the door. Except, as the petty thief is surrounded by security, he points out that he is in handcuffs so couldn't possibly steal anything. Moreover, he shows them a photo of HIV and states, "If you think I'm bad, this guy's a serial killer; he's the one you really want."

Once stimulated, the immune cells are ready for the second step -- or the instructions to recognize HIV. Given the variability of HIV, how can we teach the T-lymphocytes to recognize HIV so that a vaccine will be effective worldwide? The primary method to convey the message is by using DNA, which is like the instruction manual for your cells to make specific proteins. In this case the specific proteins are similar to those found on the surface of or inside HIV, including proteins called env, gag, pol, nef and tat. This is either injected directly as "naked" DNA or hidden inside another virus or viral vector.

Once inside the cell, production of these proteins can ultimately train the T-lymphocytes to recognize these HIV proteins. Each vaccine has its own recipe often based on one of the HIV subtypes. It could be as simple as just subtype B gag or as complicated as multi-subtype env plus subtype B gag, pol and nef. Finally, for most vaccines the lesson has to be repeated for it to endure, although how many times and how often remain prominent questions. Current studies adopting this approach vary, but generally include a multiple vaccination schedule, such as three vaccinations over a two-month period or four vaccinations over a six-month period.

Each of the current vaccine studies will help solve one small piece of the puzzle, such as:

which adjuvant is the best stimulant;

whether the DNA should be naked or packaged in adenovirus or MVA vectors;

whether vaccine design (e.g., the lesson) should be simple or complex;

whether changing the dosing frequency improves the response.

Alternatively, studies may reveal the path to an entirely novel approach. It is only through the true collaboration of researchers with international networks such as the HIV Vaccine Trials Network, the International AIDS Vaccine Initiative, and other similar research agencies that the pieces of the puzzle may slowly be completed to speed the process of finding an effective vaccine to prevent HIV.

Angela Talley, M.D. is a sub-investigator and Steven Chang, ANP is a site coordinator with the Columbia University Medical Center site of the NYC HIV Vaccine Trials Unit.

A note from TheBody.com: The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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